Early response to radiotherapy and immunotherapy in rectal cancer: an integrated molecular, cellular, and spatial approach

直肠癌放疗和免疫治疗的早期反应：综合分子、细胞和空间方法

基本信息

批准号：
10737592
负责人：
Todd A Aguilera
金额：
$ 65.67万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737592
关键词：
Acceleration Agonist Animal Model Antibodies Biopsy Chemotherapy and/or radiation Clinical Clinical Trials Clinical assessments Colorectal Cancer Combination immunotherapy Complex Coupled Data Set Dendritic Cells Development Disease Management Evaluation Event Experimental Models Future Histologic Human Immune Immune Targeting Immune response Immune signaling Immunofluorescence Immunologic Immunotherapy In complete remission Incidence Individual Innate Immune Response Knowledge Learning Local Therapy Malignant Neoplasms Maps Mismatch Repair Deficiency Modeling Molecular Neighborhoods Neoadjuvant Therapy Operative Surgical Procedures Pathway interactions Patient Selection Patients Pharmacodynamics Phase Population Proteomics Radiation Radiation therapy Rectal Cancer Risk Reduction Signal Transduction Systemic Therapy TNFRSF5 gene Technology Therapeutic Therapeutic Effect Tissues Tumor Tissue Validation adaptive immune response anti-tumor immune response cancer immunotherapy chemotherapy curative treatments deep learning efficacy testing enhancing factor evidence base high risk immunogenic immunotherapy trials improved improved outcome innovation insight novel participant enrollment patient population patient response permissiveness personalized medicine phase II trial precision oncology radiation response randomized trial randomized, clinical trials receptor responders and non-responders response single-cell RNA sequencing success synergism therapy development treatment response trial design tumor tumor microenvironment

项目摘要

Project Abstract With increased incidence in young populations and ~65% three-year survival of high-risk locally advanced rec- tal cancer, innovative approaches to improve outcomes is imperative. Neoadjuvant therapy with radiation (RT) and chemotherapy (CT) is now the standard curative treatment, but there is demand for non-operative man- agement (NOM) if the disease can be cured with local and systemic therapy. Thus, innovations could be trans- formative with the aim to improve durable complete responses by personalizing therapy, which includes how to deliver RT, CT, and the incorporation of novel agents such as immunotherapy. Cancer Immunotherapy has had little impact on colorectal cancer outside of mismatch repair deficient tumors. The αCD40 agonist antibody is an emerging class of immunotherapy and sotigalimab has shown promise in phase I and multiple ongoing phase II trials. The CD40 receptor is important in both innate and adaptive immune responses and a greater therapeutic effect can be achieved combining αCD40 with RT in animal models. We hypothesize that short course RT (SCRT) and CT when combined with αCD40 in human tumors can result in a greater antitumor im- mune response, reduce risk of metastatic progression, and extend survival in a poorly immunogenic malig- nancy like rectal cancer. We developed the INNATE trial, a phase II randomized trial of neoadjuvant SCRT fol- lowed by CT with or without the addition of sotigalimab for locally advanced rectal cancer. This trial design has allowed us to collect fresh pre- and post-SCRT biopsy tissue, which we have obtained from 21 of 30 patients enrolled to date. In this proposal, we focus on the central hypothesis that an integrated molecular, cellular, and spatial assessment of treatment response dynamics in the tumor microenvironment early after SCRT can re- veal insights into the immunobiological responses, which can inform mechanisms of efficacy and therapeutic selection. We will perform 1) molecular and cellular single cell (sc) RNAseq with proteomic and immune reper- toire analysis, 2) molecular, cellular, and spatial multiplex immunofluorescence, and 3) cellular and spatial quantitative deep learning based histopathologic analysis to achieve our aims. These three technologies will enable us to investigate early changes across RT and αCD40 treated groups. Then we will aim to identify ther- apeutic opportunities for the combination of SCRT with immune active agents though an integrated RT re- sponse assessment. Lastly, we will establish innate and adaptive immunologic signaling events triggered by SCRT in combination with αCD40 immunotherapy and factors that enhance or hinder efficacy. We will use models to start validating key findings and aim to propose future therapeutic directions to build off these efforts and ultimately improve outcomes. Specifically, regarding our patient population, we expect this proposal will lead to evidenced based trials for most patients with locally advanced rectal cancer who strive to achieve cure without a morbid surgery.

项目摘要年轻人口的发病率增加，高危局部晚期恢复的三年生存率为65％ TAL癌，改善预后的创新方法是辐射的新辅助治疗（RT）现在，化学疗法（CT）是标准的治疗方法，但是如果可以通过局部和全身治疗来治愈该疾病，则可以转移这种疾病。形成性的目的是通过个性化疗法来改善耐用的完整反应，其中包括如何提供RT，CT，并掺入新型药物，例如癌症免疫疗法对肿瘤不匹配的肿瘤不匹配的结直肠癌几乎没有影响。是一类富有的IMUNTHOPAY和SOTIGALIMAB在I期中表现出的希望和多个正在进行的 II期试验。可以在动物模型中将αCD40与RT相结合的治疗效果。在人类肿瘤中与αCD40结合的课程RT（SCRT）和CTWHER可能会导致更大的抗肿瘤IM- 宗教反应，降低转移性进展的风险，并延长Poory免疫原性恶性像记录癌症一样，我们开发了先天性试验由CT降低或不添加sotigalimab进行局部高级恢复。允许我们收集新的Pref-Now-SCRT活检组织，我们从30名患者中有21个发现了这一点迄今为止注册了。在SCRT之后，早期肿瘤微环境中治疗反应动态的空间评估可以重新评估对免疫生物学反应的小牛肉见解选择。我们将执行1）分子和细胞单细胞（SC） TOIRE分析，2）分子，细胞和空间多重荧光，以及3）细胞和空间基于深度学习的组织病理学分析以实现我们的目标使我们能够研究RT和αCD40治疗组的早期变化。辅助RT的辅助剂与Imune剂结合在一起 Spone评估。 SCRT与αCD40免疫疗法和增强功效的因素结合使用开始验证关键发现并旨在提出未来的治疗方向的模型并没有提高最终结果。导致大多数高级直肠canctal canctal canctal canctal canctal canctal canctal canctal canctal canctal canctal Cure Cure Cure固化的基于证据的试验没有病态手术。